Previous attempts to prepare cyclopropylacetonitrile have proceeded via cyanide displacement of the intermediate cyclopropylmethyl bromide or cyclopropylmethyl chloride. For example, Cartier and Bunce, J. Am. Chem. Soc., 85, 935 (1963) reacted cyclopropylmethyl bromide with sodium cyanide in ethanol and isolated pure cyclopropylacetonitrile in 20% yield using preparative gas chromatography. Hanak and Ensslin, Annalen, 697, 100 (1966) carried out the same reaction and reported a yield of 24%; cyclopropylmethyl chloride gave a yield of only 15%. A substantial improvement is described by Mezzoni et al., J. Med. Chem., 13, 878 (1970) wherein the reaction of cyclopropylmethyl bromide with sodium cyanide in dimethylsulfoxide at 70.degree. C. gave, after a cumbersome workup, a 76% yield of cyclopropylacetonitrile. Finally, Pardo and Morize, JCS Chem. Comm., 1982, 1037, mention, in a communication devoid of experimental data or reaction conditions, that cyclopropylacetonitrile was obtained from cyclopropylmethyl bromide in 75% yield using "phase-transfer".
Cyclopropylmethyl halide, from which the desired cyclopropylacetonitrile may be obtained, can be prepared from cyclopropanemethanol. The simplest process for preparing cyclopropylmethyl halide comprises contacting cyclopropane methanol with an aqueous hydrogen halide solution. However, this process gives a product which comprises a cyclobutyl halide (e.g., cyclobutyl bromide b.p.=108.degree. C.) and a 4-halo-1-butene (e.g., bromobutene b.p.=100.degree. C.) in addition to the desired cyclopropylmethyl halide (e.g., cyclopropylmethyl bromide b.p.=1 06.degree. C.). See, for example, Roberts and Mazur, J. Am. Chem. Soc., 72, 2509 (1951). These by-products are very difficult to separate by distillation, a problem exacerbated by the formation of azeotropes of cyclopropylmethyl halide, cyclobutyl halide, and 4-halo-1-butene with common organic solvents. Thus, Cartier and Bunce (vide supra) reacted cyclopropane methanol with PBr.sub.3 at -20.degree. C. to give cyclopropylmethyl bromide contaminated with cyclobutyl bromide and bromobutene. Other workers have avoided the contamination and separation problems by using more selective reagents for converting cyclopropane methanol to cyclopropylmethyl halide. For example, Mitani et al., European Patent Application EP 0 858 988 A1 convert cyclopropane methanol to an intermediate sulfonate ester which is then displaced with bromide ion to give cyclopropylmethyl bromide in good yield and purity. Hrubiec and Smith, J. Org. Chem., 49, 431 (1984) used bromine in the presence of triphenylphosphine and dimethylformamide to transform cyclopropane methanol into cyclopropylmethyl bromide. It is apparent that all of these methods for the synthesis of cyclopropylmethyl halide suffer from the need for difficult separations, use intermediate compounds such as sulfonates, or generate wastes which are difficult to handle, e.g., triphenylphosphine oxide. However, the preferred method for preparing cyclopropylmethyl halide for use in producing the subject nitrile would be the reaction of cyclopropane methanol with aqueous hydrogen halide, if the problem of isomer separation could be overcome. As in the case of halide compounds cyclopropylmethyl halide, cyclobutyl halide, and 4-halo-1-butene, the nitrile (or cyano) compounds corresponding to cyclopropylmethyl halide, cyclobutyl halide, and 4-halo-1-butene also are virtually impossible to separate on a commercial scale.
Cyclobutyl halide of acceptable purity also is difficult to obtain. As mentioned above, reaction of the alcohol (i.e., cyclopropane methanol) with aqueous hydrogen halide leads, through rearrangement chemistry, to an appreciable amount of cyclobutyl halide. However, cyclobutyl halide cannot be separated on commercial scale from the co-produced cyclopropylmethyl halide and 4-halo-1-butene. Pure cyclobutyl halide apparently is best prepared by a multistep procedure proceeding via a Hunsdiecker reaction of cyclobutanecarboxylic acid (DuPont et al., Syn. Comm., 20, 1011 (1990)). This process affords cyclobutyl halide contaminated by a 5-8% of cyclopropylmethyl halide and uses stoichiometric amounts of expensive silver nitrate reagent and toxic carbon tetrachloride solvent.